A fundamental gap exists between acute graft versus host disease (GVHD) rates (up to 50%) and the related mortality (up to 50%) following allogeneic hematopoietic cell transplantation (HTC) and the paucity of therapies and biological correlative studies offered. This gap represents an important problem, because until it is filled, therapies will be limited to the nonspecific steroidal targeting of effector cells, and the understanding of the immunologic pathways involved in therapy-resistant GVHD will remain underexplored. Our long-term goal is to identify and validate GVHD biomarkers with the potential for risk stratification and therapeutic targeting in both adult and pediatric population. Our objective in this application is to investigate validated biomarkers of acute and chronic GVHD in a pediatric multicenter prospective trial. Our central hypothesis is that plasma biomarker panels predict acute and chronic GVHD and their impact on survival. This hypothesis was formed based on our preliminary data characterizing a panel of seven biomarkers in a predominantly adult population [interleukin-2- receptor-alpha, tumor-necrosis-factor-receptor-1, interleukin-8, hepatocyte growth factor, elafin, a skin-specific marker, regenerating islet-derived 3-alpha, a gastro-intestinal specific marker, and suppression of tumorigenicity 2] that allows acute GVHD diagnosis with good specificity and sensitivity and provides important prognostic information including survival. Similarly, a panel of five chronic GVHD proteins [monokine induced by interferon-gamma (CXCL9), elafin, interleukin-2-receptor-alpha, soluble B-cell-activating factor (sBAFF), and soluble CD13] diagnoses chronic GVHD. The rationale for this study is that once we are able to identify children who will not respond to traditional treatments and who are at particularly high risk for subsequent morbidity and mortality, we can propose personalized treatment plans that are most effective if introduced early. This hypothesis will be tested with three specific aims: 1) Create a pediatric multicenter clinic-biological repository for proteomic biomarkers. 2) To validate proteomic biomarkers of acute and chronic in the pediatric population. 3) Create an integrated clinically useful protein biomarker panel of GVHD. This approach is innovative because it creates for the first time a large pediatric multicenter repository containing both clinical data and bio specimens that will allow bridging pediatric and adult knowledge and therapeutics in complications post-HCT. The proposed research is significant because the identification of GVHD biomarker panels at symptom onset or earlier is expected to impact our ability to risk stratify patients before initiating GVHD treatment. It will lso guide the intensity and duration of treatment, and help minimize the toxicity associated with chronic steroid administration. Ultimately, we propose the discovery of a GVHD-specific drug to increase efficacy and lower toxicity.